Within the hippocampus, a region of the brain important for some types of learning and memory, the strength of excitatory synapses onto CA1 pyramidal cells is persistently altered following certain patterns of synaptic activity. Long-term potentiation, a persistent enhancement of synaptic transmission that occurs at these synapses, is currently a leading candidate for a cellular mechanism involved in memory formation. On the basis of theoretical arguments it has been proposed that, in addition to long-term potentiation, the synaptic processes involved in memory may also include mechanisms that produce a long-term depression of synaptic transmission. Consistent with this prediction, two different types of homosynaptic LTD have been observed in the hippocampus. However, while LTD of basal synaptic transmission is a prominent phenomenon in the hippocampus of young animals,it is rarely seen at synapses in the CA1 region of the adult hippocampus. Thus these two forms of homosynaptic LTD may primarily be developmental forms of synaptic plasticity and are probably unlikely to contribute to the synaptic processes involved in memory in the adult hippocampus. Although not yet well understood, there is one form of long-term depression, known as depotentiation, that occurs at synapses in the adult hippocampus. Depotentiation refers to the persistent depression of synaptic transmission that occurs following low-frequency stimulation of synapses that have recently undergone LTP. Since depotentiation selectively occurs at synapses that have undergone LTP in the adult hippocampus, it may have an important role in hippocampal-dependent memory formation. Thus, the specific aim of the experiments described in this proposal is to identify the synaptic and molecular processes responsible for depotentiation. Electrophysiological techniques will be used to study synaptic transmission in the adult hippocampus and pharmacological manipulations will be used to probe the signal transduction pathways involved in depotentiation. Moreover, depotentiation will be studied in transgenic mice expressing a mutant form of a calcium/calmodulin-dependent kinase II, a protein kinase that may be an important modulatory role in hippocampal synaptic plasticity. The proposed experiments focus on depotentiation since to fully understand the cellular basis of memory in the adult hippocampus, it will be necessary to identify the synaptic and biochemical processes involved in forms of synaptic plasticity, such as depotentiation, that are present in the adult hippocampus. Moreover, understanding these processes will be important understanding, at the cellular level, how memory is impaired in pathological conditions such as Alzheimer's disease.